Project Summary/Abstract Aging is a body-wide process. As animals and humans get older, all the tissues/organs age and lose functions, albeit at different rates, resulting in an increased probability of death. Tissue-tissue communications via cell non-autonomous signaling play a key role in choreographing such a body-wide process. Recent work has pointed to an increasingly important role of the nervous system in coordinating tissue-tissue communication during aging. However, the underlying mechanisms are not well understood. One major challenge lies in the immense complexity of the nervous system. As such, model organisms with a smaller nervous system, such as C. elegans and Drosophila, have emerged as excellent models for studying this phenomenon. Importantly, the genetic pathways that modulate aging tend to be conserved in these model organisms. Furthermore, the wiring diagram (connectome) of the C. elegans nervous system has been completely mapped out, offering a unique advantage. Despite its small size, the molecular and cellular makeup of the worm nervous system is very similar to that of mammals, including their sharing of a similar set of neurotransmitters, receptors and ion channels that underlie neurotransmission. Nevertheless, even for such a simple organism as C. elegans, it remains largely unclear how its nervous system coordinates tissue-tissue communications during aging via cell non-autonomous signaling. Previous work from many groups has extensively characterized the role of neuropeptides in aging, particularly insulin-like peptides (ILPs). However, whether and how canonical neurotransmitters, which are the primary intercellular signaling molecules in the nervous system, modulate aging is much less clear. We have recently begun to study this important question by conducting the first comprehensive analysis of all canonical neurotransmitters for their roles in aging. Our preliminary studies reveal complex nervous system-gut communications via distinct neurotransmitters in longevity signaling. In the current proposal, we will focus on characterizing how the neurotransmitters GABA, ACh and serotonin released from different groups of neurons signal the distal tissue gut to regulate longevity in a cell-non-autonomous manner. We will investigate the underlying molecular and cellular mechanisms by testing several hypotheses. To do so, we will leverage our expertise in both neuroscience and aging. As aging mechanisms tend to be evolutionarily conserved, the proposed work will provide novel insights into cell non- autonomous aging in mammals.